Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000623522 | SCV000743048 | pathogenic | Inborn genetic diseases | 2023-10-17 | criteria provided, single submitter | clinical testing | The c.10658T>C (p.I3553T) alteration is located in exon 61 (coding exon 60) of the PKHD1 gene. This alteration results from a T to C substitution at nucleotide position 10658, causing the isoleucine (I) at amino acid position 3553 to be replaced by a threonine (T). Based on data from gnomAD, the C allele has an overall frequency of 0.003% (1/31404) total alleles studied. The highest observed frequency was 0.007% (1/15430) of European (non-Finnish) alleles. This variant has been reported in trans with a second PKHD1 variant in multiple individuals diagnosed with autosomal recessive polycystic kidney disease (Ward, 2002; Obeidova, 2015; Szabó, 2018). This amino acid position is poorly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. |
| Labcorp Genetics |
RCV000004329 | SCV001414655 | pathogenic | Autosomal recessive polycystic kidney disease | 2023-12-21 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3553 of the PKHD1 protein (p.Ile3553Thr). This variant is present in population databases (rs137852948, gnomAD 0.007%). This missense change has been observed in individual(s) with polycystic kidney disease (PKD) (PMID: 11919560, 29956005). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4113). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV003415648 | SCV004115406 | likely pathogenic | PKHD1-related disorder | 2023-08-25 | criteria provided, single submitter | clinical testing | The PKHD1 c.10658T>C variant is predicted to result in the amino acid substitution p.Ile3553Thr. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524266-A-G). This rare variant has been reported in the compound heterozygous state with different pathogenic variants in individuals with autosomal recessive polycystic kidney disease (ARPKD) (Ward et al. 2002. PubMed ID: 11919560; Obeidova et al. 2020. PubMed ID: 32574212). This variant is interpreted as likely pathogenic. |
| Baylor Genetics | RCV003460425 | SCV004204600 | pathogenic | Polycystic kidney disease 4 | 2024-02-21 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000004329 | SCV000024500 | pathogenic | Autosomal recessive polycystic kidney disease | 2002-03-01 | no assertion criteria provided | literature only | |
| Counsyl | RCV000004329 | SCV000800507 | uncertain significance | Autosomal recessive polycystic kidney disease | 2017-03-16 | flagged submission | clinical testing |